My major goal is to elucidate host mechanisms involved in the efficient control of virus infections, studying as a model the natural host-virus relationship of polyomavirus (PyV)-infected mice. We previously reported that PyV, a DNA tumor virus, induced protective antiviral antibody responses in the absence of T lymphocytes in T cell-deficient (TCR?x? KO) mice. This was the first report of T cell-independent (Tl), protective IgG responses to a virus. Subsequent studies with other viruses suggested that the ability to elicit Tl antibody responses may be a general phenomenon for viruses. We characterized the Tl antibody responses to PyV and mechanisms involved in their induction and showed that Tl type 2 IgG responses were induced, but only by live PyV infection, not by immunization with viral proteins or virus-like particles. Investigating how the innate immune system may collaborate with B cells to generate these responses, we have made two novel observations: (i) T cell-depleted MyD88 KO spleen cells fail to generate PyV-specific Tl IgG responses in vivo, although they respond with antiviral IgM secretion, suggesting a dependence of Tl isotype switching on innate toll-like receptor (TLR)-derived signals;(ii) long-term antiviral antibody responses were impaired in MyD88 KO mice, suggesting that T cell-dependent (TD) antiviral B cell memory to PyV infection also required MyD88-dependent signals. Based on these observations we propose to test the hypothesis that innate immune signals mediated by MyD88 are essential for the generation of antiviral Tl isotype-switched IgG responses and for long-term TD B cell responses to PyV infection. I propose to determine in which cell type(s) the MyD88-mediated signals are required for these processes, which innate receptors are involved, and investigate some of the underlying mechanisms. In addition, I plan to determine the biological consequences of impaired innate immune signaling in normal and T cell-deficient PyV-infected host by testing virus load, pathology, and possible effects on NK and ?? T cell responses. The new information generated by these studies is relevant to basic problems of viral pathogenesis that have clinical importance, such as the control of persistent virus infections (e.g. JC and BK human polyomavirus infections), particularly in hosts with partial immunodeficiency. Moreover, the proposed project will address for the first time the role of innate immune receptors in the regulation of protective antiviral Tl and long-term TD memory B cell responses in vivo, and the mechanisms involved. These basic questions are important for the design of vaccines with high efficacy.